Age-Related Macular Degeneration (AMD) is the leading cause of blindness in the United States, yet few therapeutics are approved to treat this disease. Due to an aging population, the need to develop novel tools to treat diseases of the eye with greater efficiency is a rising area of interest. One of the most promising new therapeutic strategies to treat eye disease is gene therapy using Adeno-Associated Virus (AAV). AAV is a nonpathogenic, non-integrating virus that can be used to deliver therapeutic transgenes to healthy or diseased tissues to prevent or treat disease, respectively. While current AAV vectors achieve partial transgene expression, vector development is necessary to achieve complete and universal treatment. The field is currently impeded by a reliance on subretinal injections, which are invasive and deliver therapeutics to a limited area in the retina. Currently no satisfactory AAV vectors exist to mediate therapeutic transgene expression in the retina via intravitreal injection, a less invasive procedure that can potentially result in global gene expression across the entire retina. This proposal outlines the evaluation of novel designer AAV vectors, engineered by the Samulski lab, for transgene delivery to the retina via intravitreal injection. Experiments will be performed to select the most promising vector candidates based on delivery upon intravitreal injections to the healthy and diseased mouse retina. Experiments are also proposed that will utilize a novel AAV vector for the delivery of a therapeutic transgene to a degenerating mouse retina. In addition to optimizing gene therapy for intravitreal retinal delivery, testing our AAV vectors in a retinopathy model at aged time points will provide valuable information about gene therapy in older adults, an area that has not been very well explored. These experiments will be conducted using a Nrf2-deficient mouse that exhibits an age-related retinopathy similar to AMD in humans. Nrf2 is significant in that it is involved in the regulation f oxidative stress, the deregulation of which is commonly thought to play a large role in the pathogenesis of AMD. In these experiments, AAV will be used to deliver Nrf2 to retinas of acutely stressed or naturally aged Nrf2-/- mice. From these experiments we hope to use AAV vectors to explore the contribution of oxidative stress to the pathogenesis of retinal disease, and the therapeutic potential of AAV-Nrf2 for treatment of retinal degeneration. If funded, these studies will pioneer the development of novel AAV vectors for safe and effective retinal gene therapy, and address important unanswered questions about the role of oxidative stress in retinal degeneration. The proposed training and research plans will provide a solid educational and professional foundation on which to pursue a career as a physician scientist in the field of translational Ophthalmology.